Approximately 60 million Americans have skin disorders requiring medical treatment each year. The long-term objective of this project is to develop a commercial product(s) for the topical treatment of acne and skin diseases. The specific aim of the proposal is to invent a prodrug that can be used effectively and safely for the topical treatment of acne. Isotretinoin (13-cis-retinoic acid, Accutane-Roche) administered orally gives birth defects and applied topically is irritating. We designed prodrugs of isotretinoin to solve this systemic toxicity problem by delivering the therapeutic dose directly to the target organ (skin). Nine prodrugs were synthesized and evaluated during Phase I. Eight are as effective as isotretinoin in the topical rhino mouse assay. These promising candidates are undergoing further biological evaluation. These novel prodrug moieties have application in other medical areas. Our Phase I grant has been supplemented by $100,000 from the private sector and has produced a U.S. patent application. An Investigational New Drug application is in preparation. We have a $1,000,000 committment from Owen Laboratories for Phase III funding. Phase II support is requested (1) to continue and scale up the design, QSAR, synthesis, and biological evaluation and (2) to develop and optimize the lead prodrugs.